1. Field of the Invention
The present invention relates to aporphine compounds and pharmaceutical use thereof, more particularly, to aporphine compounds that can inhibit lipid peroxidase, exert the free radical scavenging activities and protect vascular smooth muscle cells, and pharmaceutical use thereof.
2. Description of Related Art
Oxidative stress alters many functions of the endothelium. As known in the art, oxidative stress is involved in the pathogenesis of a group of diseases, such as hypercholesterolemia, atherosclerosis, hypertension, diabetes, and heart failure etc. (Cai H et al., Circ. Res. 2000; 87: 840-844), and ischemic cerebral diseases, including ischemic cerebral thrombosis, ischemic cerebral embolism, hypoxic ischemic encephalopathy etc. Department of Physiological Science. University of California also published that oxidative stress is thought to play a major role in the pathogenesis of a variety of human diseases, including atherosclerosis, diabetes, hypertension, aging, Alzheimer's disease, kidney disease and cancer (Roberts C K et al., Life Sci. 2009; 84: 705-712). In addition, a role of the free-radical processes and disturbances of oxidative-restorative blood homeostasis and nervous tissue in the pathogenesis of brain ischemic pathology and other diseases was published (Solov'eva EIu et al., Zh Nevrol Psikhiatr Im S S Korsakova. 2008; 108(6): 37-42). Recent studies also demonstrated a significant role of inflammatory processes and oxidative stress in the pathomechanism of cerebral stroke. Increased production of free radicals was observed in both the ischemic and haemorrhagic strokes and oxidative stress was shown to be one of the causative mechanisms of tissue damage in these diseases.
Oxidative stress mediates cell damage via reactive oxygen species (ROS). Oxidative stress has been identified throughout the process of atherogenesis (Warnholtz A et al., Circulation 1999; 99: 2027-2033). As the process of atherogenesis proceeds, inflammatory cells as well as other constituents of the atherosclerotic plaque release large amounts of ROS, which further facilitate atherogenesis. In general, increased production of ROS may affect four fundamental mechanisms that contribute to atherogenesis: oxidation of low density lipoprotein (LDL), endothelial cell dysfunction, growth of the vascular smooth muscle cells and monocytes migration (Berliner J A et al., Free Radic Biol Med 1996; 20: 707-727). Therefore, oxidative stress plays a decisive role in atherosclerosis. A number of studies suggest that ROS oxidatively modified LDL is a more potent proatherosclerotic mediator than the native unmodified LDL (Heinecke J W., Atherosclerosis 1998; 141: 1-15).
Atherosclerosis is the buildup of fatty deposits called plaque on the inside walls of arteries. Arteries are blood vessels that carry oxygen and blood to the heart, brain, and other parts of the body. As plaque builds up in an artery, the artery gradually narrows and can become clogged. As an artery becomes more and more narrowed, less blood can flow through.
Risk factors for atherosclerosis, such as hypertension and hyperlipidemia, are also associated with increased generation of ROS (Patterson C et al., Circ. Res. 2000; 87(12): 1074-1076). Increasing evidence shows that ischemia-reperfusion, which frequently occurs in narrowed atherosclerotic arteries, increases ROS generation (Li D et al., J Am Coll Cardiol 2003; 41: 1048-1055).
Thaliporphine, which is a phenolic alkaloid isolated from the plants of Neolitsea konishii K, is an aporphine derivative. (Teng C M et al., Eur J Pharmacol. 1993; 233(1): 7-12). It has been disclosed that thaliporphine is a positive inotropic agent with a negative chionotropic action (Su M J et al., Eur. J. Pharmacol, 1994; 254: 141-150). In animal coronary artery occlusion study, thaliporphine reduces occurrence of arrhythmia and mortality during ischemia and ischemia-reperfusion. It also attenuates cardiac infarct zone after long term ischemia. Besides, thaliporphine inhibits low density lipoprotein (LDL) peroxidation and exerted the scavenging activities of superoxide anion. Particularly, thaliporphine significantly increases NO and decreases lactate dehydrogenase (LDH) levels in the blood during the end period of ischemia or ischemia-reperfusion (I/R). Thus, thaliporphine can reduce ischemia or I/R-induced cardiac injury. Accordingly, the multifactorial beneficial effects of thaliporphine may afford an opportunity of being used as an effective antiarrhythmic and cardioprotective agent (Hung L M et al., Drug Dev. Res. 2001; 52: 446-453). In addition, thaliporphine could be a novel agent for attenuating endotoxin-induced circulatory failure and multiple organ injury, and may increase the survival rate (Chiao C W et al., Naunyn Schmiedebergs Arch Pharmacol. 2005; 371(1): 34-43).
U.S. Pat. No. 6,313,134 disclosed thaliporphine and its derivatives for the treatment and/or prophylaxis of cardiac diseases, including cardiac arrhythmia, myocardial ischemia or myocardial infarction, and sudden death caused by cardiac arrhythmia or acute myocardial infarction.
U.S. Pat. No. 7,057,044 provided aporphine and oxoaporphine compounds that have endothelial nitric oxide synthase (eNOS) maintaining or enhancing activities and may be used to manufacture a medicaments for preventing or treating ischemic diseases in human and mammal, and the ischemic diseases may include ischemic cerebral apoplexy, ischemic cerebral thrombosis, ischemic cerebral embolism, hypoxic ischemic encephalopathy, ischemic cardiac disease or ischemic enteropathy etc.